Prefrontal gray matter volume mediates genetic risks for obesity.

Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347). Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples. Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker.

Effects of emergency medical service transport on acute stroke care.

BACKGROUND AND PURPOSE: Since early treatment of acute stroke is associated with an improved outcome, emergency medical service (EMS) transport of stroke patients is recommended. It remains unclear, however, whether EMS transport leads to faster treatment. The impact of the transport mode on pre- and in-hospital processes of care was therefore investigated. METHODS: The present study was based on a prospective database of 158 hospitals of the Stroke Register of Northwestern Germany, which included 162,511 stroke patients admitted between January 2010 and December 2011. Main outcome measures were the baseline characteristics associated with EMS transport and process-of-care indicators according to the transport mode. RESULTS: Overall, 101,850 (72.0%) patients were transported by EMS and 39,324 (28.0%) by self-transport. The baseline characteristics showing the strongest associations with EMS use were the care situation [institutional care, adjusted odds ratio (OR) 7.81; 95% CI 6.86-8.90], a disturbed level of consciousness (adjusted OR 3.00; 95% CI 2.59-3.48) and having a subarachnoid (adjusted OR 2.79; 95% CI 2.24-3.49) or intracerebral hemorrhage (adjusted OR 2.26; 95% CI 1.92-2.67). For self-transport patients the probability of being in a higher onset-to-door time category was 4.36 (95% CI 4.26-4.47) and the probability of being in a higher door-to-imaging time category was 1.32 (95% CI 1.28-1.36). Compared with self-transport, EMS transport was independently associated with thrombolysis (adjusted OR 1.95, 95% CI 1.77-2.15). CONCLUSIONS: Patient transport with EMS was independently associated with faster hospital arrival and shorter time periods from hospital admission to brain imaging and to the frequency of thrombolysis.

A statistical cerebroarterial atlas derived from 700 MRA datasets.

OBJECTIVES: The cerebroarterial system is a complex network of arteries that supply the brain cells with vitally important nutrients and oxygen. The inter-individual differences of the cerebral arteries, especially at a finer level, are still not understood sufficiently. The aim of this work is to present a statistical cerebroarterial atlas that can be used to overcome this problem. METHODS: Overall, 700 Time-of-Flight (TOF) magnetic resonance angiography (MRA) datasets of healthy subjects were used for atlas generation. Therefore, the cerebral arteries were automatically segmented in each dataset and used for a quantification of the vessel diameters. After this, each TOF MRA dataset as well as the corresponding vessel segmentation and vessel diameter dataset were registered to the MNI brain atlas. Finally, the registered datasets were used to calculate a statistical cerebroarterial atlas that incorporates information about the average TOF intensity, probability for a vessel occurrence and mean vessel diameter for each voxel. RESULTS: Visual analysis revealed that arteries with a diameter as small as 0.5 mm are well represented in the atlas with quantitative values that are within range of anatomical reference values. Moreover, a highly significant strong positive correlation between the vessel diameter and occurrence probability was found. Furthermore, it was shown that an intensity-based automatic segmentation of cerebral vessels can be considerable improved by incorporating the atlas information leading to results within the range of the inter-observer agreement. CONCLUSION: The presented cerebroarterial atlas seems useful for improving the understanding about normal variations of cerebral arteries, initialization of cerebrovascular segmentation methods and may even lay the foundation for a reliable quantification of subtle morphological vascular changes.

Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance.

The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.

The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models.

A compelling association has been observed between cardiovascular disease (CVD) and depression, suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality. Systemic immune activation, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship. Although a differential epidemiological association between CVD and depression subtypes is evident, it has not been determined if this indicates subtype specific biological mechanisms. A comprehensive systematic literature search was conducted using PubMed and PsycINFO databases yielding 147 articles for this review. A complex pattern of systemic immune activation, endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes. The findings of this review suggest that diagnostic subtypes rather than a unifying model of depression should be considered when investigating the bidirectional biological relationship between CVD and depression. The suggested model of a subtype-specific biological relationship between depression and CVDs has implications for future research and possibly for diagnostic and therapeutic processes.

[New cohorts. The BiDirect study]. / Neue Kohorten. Die BiDirect-Studie.

The BiDirect study examines the association between depression and cardiovascular diseases in an innovative design. The study has been funded by the German Minister of Research and Education since 2009. Patients, hospitalised for an acute depression episode, a random sample of the inhabitants of the city of Münster and patients with an acute coronary syndrome from the same area are recruited into three cohorts, examined in parallel with identical methods. The latter includes a psychiatric classification, including subtypes of depression, a vascular diagnostic work-up, weight and height assessments and magnetic resonance imaging (MRI) of the brain. A first follow-up will be conducted 2 years after baseline. The study design allows a comprehensive analysis of the complex and bidirectional association between subclinical arteriosclerosis and depression.

Decomposing the Hounsfield unit: probabilistic segmentation of brain tissue in computed tomography.

PURPOSE: The aim of this study was to present and evaluate a standardized technique for brain segmentation of cranial computed tomography (CT) using probabilistic partial volume tissue maps based on a database of high resolution T1 magnetic resonance images (MRI). METHODS: Probabilistic tissue maps of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) were derived from 600 normal brain MRIs (3.0 Tesla, T1-3D-turbo-field-echo) of 2 large community-based population studies (BiDirect and SEARCH Health studies). After partial tissue segmentation (FAST 4.0), MR images were linearly registered to MNI-152 standard space (FLIRT 5.5) with non-linear refinement (FNIRT 1.0) to obtain non-binary probabilistic volume images for each tissue class which were subsequently used for CT segmentation. From 150 normal cerebral CT scans a customized reference image in standard space was constructed with iterative non-linear registration to MNI-152 space. The inverse warp of tissue-specific probability maps to CT space (MNI-152 to individual CT) was used to decompose a CT image into tissue specific components (GM, WM, CSF). RESULTS: Potential benefits and utility of this novel approach with regard to unsupervised quantification of CT images and possible visual enhancement are addressed. Illustrative examples of tissue segmentation in different pathological cases including perfusion CT are presented. CONCLUSION: Automated tissue segmentation of cranial CT images using highly refined tissue probability maps derived from high resolution MR images is feasible. Potential applications include automated quantification of WM in leukoaraiosis, CSF in hydrocephalic patients, GM in neurodegeneration and ischemia and perfusion maps with separate assessment of GM and WM.

Impact of common KIBRA allele on human cognitive functions.

The rs17070145 polymorphism (C → T substitution, intron 9) of the KIBRA gene has recently been associated with episodic memory and cognitive flexibility. These findings were inconsistent across reports though, and largely lacked gene-gene or gene-environment interactions. The aim of the present study was to determine the impact of the rs17070145 polymorphism on clinically relevant cognitive domains and its interaction with the modifiers 'lifestyle' and 'cardiovascular risk factors'. Five-hundred forty-five elderly volunteers (mean age 64 years, ±7 years, 56% women) accomplished a comprehensive cognitive testing. Principal component analysis was used to reveal the internal structure of the data, rendering four composite scores: verbal memory, word fluency, executive function/psychomotor speed, and working memory. Lifestyle was assessed with a detailed questionnaire, age-associated risk factors by clinical interview and examination. There was no main effect of the rs17070145 genotype on any cognitive composite scores. However, we found worse performance in executive functions for T-allele carriers in the presence of arterial hypertension (ß=-0.365, p=0.0077 and 0.031 after Bonferroni correction). This association was further modified by gender, showing the strongest association in hypertensive females (ß=-0.500, p=0.0072 and 0.029 after Bonferroni correction). The effect of KIBRA on cognitive function seems to be complex and modified by gender and arterial hypertension.

Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function.

OBJECTIVE: C-reactive protein is a marker of inflammation and vascular disease. It also seems to be associated with an increased risk of dementia. To better understand potential underlying mechanisms, we assessed microstructural brain integrity and cognitive performance relative to serum levels of high-sensitivity C-reactive protein (hs-CRP). METHODS: We cross-sectionally examined 447 community-dwelling and stroke-free individuals from the Systematic Evaluation and Alteration of Risk Factors for Cognitive Health (SEARCH) Health Study (mean age 63 years, 248 female). High-field MRI was performed in 321 of these subjects. Imaging measures included fluid-attenuated inversion recovery sequences for assessment of white matter hyperintensities, automated quantification of brain parenchyma volumes, and diffusion tensor imaging for calculation of global and regional white matter integrity, quantified by fractional anisotropy (FA). Psychometric analyses covered verbal memory, word fluency, and executive functions. RESULTS: Higher levels of hs-CRP were associated with worse performance in executive function after adjustment for age, gender, education, and cardiovascular risk factors in multiple regression analysis (beta = -0.095, p = 0.02). Moreover, higher hs-CRP was related to reduced global fractional anisotropy (beta = -0.237, p < 0.001), as well as regional FA scores of the frontal lobes (beta = -0.246, p < 0.001), the corona radiata (beta = -0.222, p < 0.001), and the corpus callosum (beta = -0.141, p = 0.016), in particular the genu (beta = -0.174, p = 0.004). We did not observe a significant association of hs-CRP with measures of white matter hyperintensities or brain atrophy. CONCLUSION: These data suggest that low-grade inflammation as assessed by high-sensitivity C-reactive protein is associated with cerebral microstructural disintegration that predominantly affects frontal pathways and corresponding executive function.